The inducible transcription factor Nuclear Factor-kappa B (NF-κB) participates in the regulation of multiple cellular genes, including many involved in the immune and inflammatory processes (for example, GM-CSF, IL-6, IL-8 and IL-2). NF-κB is a member of the rel family of protein complexes, and is activated by cellular exposure to various factors, including phorbol 12-myristate 13-acetate (PMA), lipopolysaccharide (LPS), interleukin-1 (IL-1), tumor necrosis alpha (TNFα), and ultraviolet radiation. See Baldwin, Annu. Rev. Immunol. 14:649 (1996). NF-κB has also been implicated in the transcriptional activation of several viruses, including HIV-1 (Nabel et al., Nature 326:711 (1987); Kaufman et al., Mol. Cell. Biol., 7:3759 (1987)). The various signaling pathways that can control the activation of NF-κB are not all clearly understood. It is apparent that different inducers can initiate their pathways through distinct receptors.
The latent cytoplasmic form of NF-κB is associated with a cytoplasmic inhibitory protein called IκB. Baeuerle and Baltimore, Science 242:540 (1988); PCT US92/04073 (WO 92/20795). The release of NF-κB from IκB results in the rapid appearance of the active form of NF-κB in the cell nucleus. Genes regulated by NF-κB can be transcriptionally activated minutes after exposure of the cell to the appropriate inducer. Activation of NF-κB after exposure of a cell to an inducer is correlated with the hyperphosphorylation of IκBα and its subsequent degradation. As IκB is diminished in the cytoplasm, NF-κB increases in the nucleus. Phosphorylation of IκB was once thought to lead to dissociation from NF-κB and subsequent proteolysis of IκB. Beg and Baldwin, Genes Dev. 7:2064 (1993). More recently, it has been proposed that the proteasome is responsible for signal-mediated degradation of IκBα and IκBβ. Baldwin, Annu. Rev. Immunol. 14:649 (1996). Phosphorylation of IκB apparently renders the molecule susceptible to proteolysis.
Activation of NF-κB has been suggested as playing a pathological role in the development of autoimmune diseases and chronic inflammatory diseases such as rheumatoid arthritis, and in acute situations such as septic shock.